Anagestone acetate

Anagestone acetate, sold under the brand names Anatropin and Neo-Novum, is a progestin medication which was withdrawn from medical use due to carcinogenicity observed in animal studies.^[1][2][3]

Anagestone acetate

Clinical data
Trade names	Anatropin, Neo-Novum
Other names	ORF-1658; Anapregnone acetate; 3-Deketo-6α-methyl-17α-acetoxyprogesterone; 6α-Methyl-17α-hydroxypregn-4-en-20-one acetate
Routes of administration	By mouth
Drug class	Progestogen; Progestin; Progestogen ester
Identifiers
IUPAC name [(6S,8R,9S,10R,13S,14S,17R)-17-acetyl-6,10,13-trimethyl-1,2,3,6,7,8,9,11,12,14,15,16-dodecahydrocyclopenta[a]phenanthren-17-yl] acetate
CAS Number	3137-73-3
PubChem CID	252301
ChemSpider	221058
UNII	GNT396G9QT
KEGG	D02932
ChEBI	CHEBI:135575
CompTox Dashboard (EPA)	DTXSID50953411
ECHA InfoCard	100.019.578
Chemical and physical data
Formula	C24H36O3
Molar mass	372.549 g·mol−1
3D model (JSmol)	Interactive image
SMILES C[C@H]1C[C@@H]2[C@H](CC[C@]3([C@H]2CC[C@@]3(C(=O)C)OC(=O)C)C)[C@@]4(C1=CCCC4)C
InChI InChI=1S/C24H36O3/c1-15-14-18-20(22(4)11-7-6-8-19(15)22)9-12-23(5)21(18)10-13-24(23,16(2)25)27-17(3)26/h8,15,18,20-21H,6-7,9-14H2,1-5H3/t15-,18+,20-,21-,22-,23-,24-/m0/s1 Key:KDLNOQQQEBKBQM-DICPTYMLSA-N

Medical uses

Anagestone acetate was used in combination with the estrogen mestranol as a combined birth control pill.^[4][5]

Pharmacology

Based on its chemical structure, namely the lack of a C3 ketone, it is probable that anagestone acetate is a prodrug of medroxyprogesterone acetate (the 3-keto analogue).^[6][7]

Chemistry

See also: List of progestogens, Progestogen ester, and List of progestogen esters

Anagestone acetate, also known as 3-deketo-6α-methyl-17α-acetoxyprogesterone or as 6α-methyl-17α-acetoxypregn-4-en-20-one, is a synthetic pregnane steroid and a derivative of progesterone and 17α-hydroxyprogesterone.^[1] It is the C17α acetate ester of anagestone, which, in contrast to anagestone acetate, was never marketed.^[1] Anagestone acetate is closely related structurally to medroxyprogesterone acetate (6α-methyl-17α-acetoxyprogesterone).^[1]

History

Anagestone acetate was introduced in combination with mestranol as a birth control pill in 1968 by Ortho Pharmaceutical.^[4][5] It was withdrawn in 1969.^[5][8]

In 1969, along with a variety of other progestogens including progesterone, chlormadinone acetate, megestrol acetate, medroxyprogesterone acetate, ethynerone, and chloroethynyl norgestrel, anagestone acetate was found to induce the development of mammary gland tumors in Beagle dogs after extensive treatment (2–7 years) with very high doses (10–25 times the recommended human dose), though notably not with 1–2 times the human dosage.^[5][9][8] In contrast, the non-halogenated 19-nortestosterone derivatives norgestrel, norethisterone, noretynodrel, and etynodiol diacetate were not found to produce such nodules.^[8] Because of these findings, anagestone acetate was voluntarily withdrawn from the market by the manufacturer in 1969.^[5][8][10] The findings also led to the virtual disappearance of most 17α-hydroxyprogesterone derivatives as hormonal contraceptives from the market (though medroxyprogesterone acetate, cyproterone acetate, and chlormadinone acetate have continued to be used).^[5][9] According to Hughes et al., "It is still doubtful how much relevance these findings have for humans as the dog mammary gland seems to be the only one which can be directly maintained by progestogens."^[8][11] Subsequent research revealed species differences between dogs and humans and established that there is no similar risk in humans.^[12]

Society and culture

Generic names

Anagestone acetate is the generic name of the drug and its USANTooltip United States Adopted Name.^[1] It is also known by its developmental code name ORF-1658.^[1]

Brand names

Anagestone acetate was marketed under the brand names Anatropin and Neo-Novum, the latter in combination with the estrogen mestranol.^[1]

Availability

Anagestone acetate was withdrawn from the market and is no longer available.^[5][8][10]

See also

• Acetomepregenol

References

1. Elks J (14 November 2014). The Dictionary of Drugs: Chemical Data: Chemical Data, Structures and Bibliographies. Springer. pp. 85–. ISBN 978-1-4757-2085-3.
2. William Andrew Publishing (22 October 2013). Pharmaceutical Manufacturing Encyclopedia, 3rd Edition. Elsevier. pp. 322–. ISBN 978-0-8155-1856-3.
3. IARC Working Group on the Evaluation of Carcinogenic Risks to Humans (1987). IV. OESTROGEN-PROGESTIN COMBINATIONS. International Agency for Research on Cancer. Retrieved 24 June 2022.
4. Schreiner WE (6 December 2012). "The Ovary". In Labhart A (ed.). Clinical Endocrinology: Theory and Practice. Springer Science & Business Media. pp. 571–. ISBN 978-3-642-96158-8.
5. Streffer C, Bolt H, Follesdal D, Hall P, Hengstler JG, Jacob P, et al. (11 November 2013). "Interspecies Extrapolation". Low Dose Exposures in the Environment: Dose-Effect Relations and Risk Evaluation. Springer Science & Business Media. pp. 135–. ISBN 978-3-662-08422-9.
6. Fraser IS (1998). Estrogens and Progestogens in Clinical Practice. Churchill Livingstone. p. 281. ISBN 978-0-443-04706-0. Progestational activity depends on the presence of a 3-keto group in ring A of the steroid skeleton. Most of the progestogens used today do indeed carry such a group in their original molecules. However, the 3-keto group is initially missing in the case of desogestrel and norgestimate. They are prodrugs which undergo metabolic conversion to active 3-keto derivatives in the body.
7. McRobb L, Handelsman DJ, Kazlauskas R, Wilkinson S, McLeod MD, Heather AK (May 2008). "Structure-activity relationships of synthetic progestins in a yeast-based in vitro androgen bioassay". The Journal of Steroid Biochemistry and Molecular Biology. 110 (1–2): 39–47. doi:10.1016/j.jsbmb.2007.10.008. PMID 18395441. S2CID 5612000. Prodrugs (lack 3-keto): Ethylestrenol, Lynestrenol, Ethynodiol, Allylestrenol, Norgestimate
8. Casey HW, Giles RC, Kwapien RP (1979). "Mammary Neoplasia in Animals: Pathologic Aspects and the Effects of Contraceptive Steroids". Carcinogenic Hormones. Vol. 66. pp. 129–160 (149). doi:10.1007/978-3-642-81267-5_4. ISBN 978-3-540-08995-7. PMID 107546. {{cite book}}: |journal= ignored (help)
9. Diczfalusy E (July 1979). "Gregory Pincus and steroidal contraception: a new departure in the history of mankind". Journal of Steroid Biochemistry. 11 (1A): 3–11. doi:10.1016/0022-4731(79)90271-1. PMID 385985.
10. Consolidated List of Products Whose Consumption And/or Sale Have Been Banned, Withdrawn, Severely Restricted Or Not Approved by Governments. United Nations Publications. 1983. pp. 25–. ISBN 978-92-1-130230-1.
11. Gräf KJ, Brotherton J, Neumann F (27 November 2013). "The Clinical Uses of Antiandrogens". In Hughes A, Hasan SH, Oertel GW, Voss HE, Bahner F, Neumann F, et al. (eds.). Androgens II and Antiandrogens / Androgene II und Antiandrogene. Springer Science & Business Media. pp. 531–. ISBN 978-3-642-80859-3.
12. Runnebaum BC, Rabe T, Kiesel L (6 December 2012). "Development of Progestogens". Female Contraception: Update and Trends. Springer Science & Business Media. pp. 134–135. ISBN 978-3-642-73790-9.